CN102458455B - Factor vii composition - Google Patents
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- CN102458455B CN102458455B CN201080028582.4A CN201080028582A CN102458455B CN 102458455 B CN102458455 B CN 102458455B CN 201080028582 A CN201080028582 A CN 201080028582A CN 102458455 B CN102458455 B CN 102458455B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6437—Coagulation factor VIIa (3.4.21.21)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21021—Coagulation factor VIIa (3.4.21.21)
Abstract
The invention relates to a stable pharmaceutical composition in liquid or solid forms, including a factor VII, said composition being free of mannitol and saccharose, as well as of any antioxidant agent.
Description
Technical field
The present invention relates to the stable pharmaceutical composition of Coverage factor VII (FVII).
Background technology
Condensation phenomenon comprises the cascade enzyme reaction relating to coagulation factor, and wherein several coagulation factor is the protease comprising serine in its avtive spot.Final step is transformed into former for soluble fibrin the fiber protein yarn holding circulating cells in network structure.The numeral of coagulation factor from I to XIII, except participating in the FXIII of the final step of condensation, other factors participate in condensing with the order contrary with their numbering; Therefore, factor XI, plasma thromboplastin antecedent I starts condensation, and factor I stops it.Often kind of factor all exists with the precursor forms of non-activity with by the activated form that alphabetical a represents.
Condensation relates to two approach, and one is intrinsic pathway, and another is extrinsic pathway, produces common final approach.Two kinds of machine-processed combinations are guaranteed to form solid and flexible blood clot, and it can be resisted blood pressure and ensure enough mobilitys at the same time.Under the effect of thrombin, the chemical modification of Fibrinogen experience, causes forming fibrin.It is necessary that fibrin is that grumeleuse is formed.
Intrinsic pathway comprises the factor existed in circulation, and condensation process just starts at Ink vessel transfusing.A part for extrinsic pathway relates to and not usually being present in circulation but the tissue factor discharged during blood vessel injury.When this approach is activated, chain reaction occurs, the coagulation factor activated during this period causes the activation of follow-up coagulation factor.This approach relates to the intervention of the factor Ⅴ II (FVII) existed in blood plasma.The factor Ⅴ II of activation, also referred to as proconvertin, be one of factor participating in blood clotting mechanism, it has the molecular weight of about 50kDa.It is a kind of glycoprotein of serine stretch protein enzyme family, and the synthesis of its activated form is vitamin k-dependent.In order to cause condensation cascade reaction, FVII must be activated into FVIIa.Independent FVIIa (non-compound) has weak proteolytic activity.Then, after activation, FVIIa and tissue factor (TF) compound, this tissue factor is the cardiolipin binding protein discharged during blood vessel injury.Factor X is transformed into factor Xa by FVIIa-TF complex subsequently under calcium ion exists.This complex also acts on the activation of FIX to FIXa, thus catalyzing endogenous property approach.Factors IX a and Xa activates again the factor Ⅴ II of activation.With activation factor FV and with the factor Xa of prothrombinase compound, prothombin is become thrombin.Then thrombin action is in Fibrinogen to be converted into fibrin, and also allows to activate FVIIIa and FVa from FVIII and FV respectively.The partial function of thrombin is when there is calcium, can activation factor XIIIa, contributes to reinforcing fiber fibrin clot.
But when lacking coagulation factor, cascade reaction interrupts or defectiveness, it can describe with term condensation is extremely next.
Under the tissue factor discharged after the tissue injury caused bleeding exists, even if when there is not Factor IX or IX, the factor Ⅴ II of activation plays a role in local.Therefore, be preferably in the factor Ⅴ II of activated form, be used to treat some for a long time and show as hemorrhage coagulation disorder.This factor participates in many pathological conditions, such as wherein patients goes out A type or haemophilia B, acquired Hemophilia or the congenital factor VII Defect of Factor IX or IX inhibitor, and as stoping at the contingent hemorrhage product of surgery.
It is at present, obtainable on market that to be used for the treatment of these medicines suffering from the patient of hemophilia or congenital factor VII Defect be known.It is produced by Danish company NovoNordisk
it went through in Europe listing from 1996, and went through in 1999 to go on the market in the U.S..
the medicine of to be active component be eptacog alfa (the recombined human activation coagulation factor VII from BHK baby hamster kidney cell is produced by genetic engineering).This product is also containing sodium chloride (2.92g/l), calcium chloride dihydrate (1.47g/l), glycylglycine (1.32g/l), polysorbate 80 (0.07g/l) and mannitol (30g/l).
Also exist and be called as
the version of the NovoSeven of RT, it can make product store under room temperature (25 DEG C).This second product contains sodium chloride (2.92g/l), calcium chloride dihydrate (1.47g/l), glycylglycine (1.32g/l), polysorbate 80 (0.07g/l), mannitol (25g/l) and for regulating hydrochloric acid and the sodium hydroxide of pH, and comprises sucrose (10g/l) and methionine (0.5g/l) (as antioxidant).This product is resetted into solution and needs water for injection, but also need histidine.
rT went through in 2008 in Europe and U.S.'s listing.
The primary treatment indication of restructuring FVIIa (rFVIIa) relates to treats spontaneous hemorrhage or operative hemorrhage in the haemophilia A patient developing anti-factor VIII antibody and the haemophilia B patient having developed anti-factor IX antibody.In Europe, it is also instructed to for suffering from congenital FVII deficiency disease and the patient suffering from the graceful thrombasthenia of Glan thatch.In addition, a large amount of publication reports rFVIIa both not having the congenital deficiency disease of coagulation factor not to be had in the patient of thrombasthenia yet, the effectiveness in control during operation process hemorrhage.
Nedergaard etc., 2008 [Nedergaard H. etc., be formulated for the vitro stability (In vitro stabilityof lyophilized and reconstituted recombinant activated factor VIIformulated for storage at room temperature) of the factor Ⅴ II of the activation of the lyophilization of room temperature storage and the restructuring of reconstruct, Clinical Therapeutics, Vol 30, No.7, p1309-1315,2008] article teaches
rT is under its freeze-dried, and kept stable at 25 DEG C in 24 months, at 30 DEG C, in 12 months, at 40 DEG C, in 6 months and at 50 DEG C and 60 DEG C, in 12 hours, maintenance is stable.In addition, this product only stablizes 6 hours after the reconstruct of its liquid, therefore recommends to inject in 3 hours after reconstitution.Therefore, due to this stability, this product demonstrates operating difficulties and restriction in administration time.
Patent EP 1210361 discloses glycylglycine for the stable advantage of the freeze-dried composition of the factor Ⅴ II making activation.
Patent application WO 2004/000347 proposes other stabilizing agents various.
Soenderkaer S. etc., 2004 [Soenderkaer S. etc., sucrose is assembled and methionine oxidized impact (Effects of sucrose on rFVIIa aggregation andmethionine oxidation) rFVIIa, European Journal of Pharmaceutical Sciences, Vol21, p597-606,2004] publication describe sucrose as required excipient for the factor Ⅴ II of stable activation with to resistant to aggregation and thermal denaturation.According to this teachings, by repelling sugar can increase the chemical potential of molecule from protein surface, sucrose can make protein in aqueous solution, keep its native form.As a result, and by reducing its surface area, albumen maintenance compact configuration.Existence as the sucrose of excipient can make the factor Ⅴ II of the activation of freeze-dried stablize.
But the existence of sucrose causes introducing anti-oxidizing compounds in the formulation, cause the technology relevant to adding such compound and regulatory limits.
Therefore, at present, for exploitation containing factor Ⅴ II, not there is chemistry and physical stability containing antioxidant, at room temperature and be convenient to the medicine that patient that patient particularly suffers from hemophilia or congenital factor VII Defect uses, there is real demand.
Summary of the invention
The invention provides the pharmaceutical composition taking liquid form or solid form, its Coverage factor VII, preferably factor VIIa form, and described compositions is not containing mannitol and sucrose.
According to a preferred embodiment, compositions is not also containing any antioxidant.
Under preferable case, compositions comprises at least one hydrophilic amino acid or the aminoacid with positively charged side chain, such as arginine.
According to a preferred embodiment, compositions Coverage factor VII of the present invention, at least one hydrophilic amino acid or with the aminoacid of positively charged side chain, at least one hydrophobic amino acid and alkali metal salt, alkali salt or transition metal salt, described compositions is not containing mannitol and sucrose.
Under vantage, the compositions of solid form can take the form of powder or cake (or plug shaped article).Compositions preferably has the moisture being less than or equal to 3%.According to a specific embodiments, compositions takes freeze-dried.
Another theme of the present invention is the method preparing this compositions, and described method comprises and mixed with buffer solution by FVII, adjusts pH if necessary, and carries out filtering to obtain liquid form.This liquid form can experience drying subsequently to obtain solid form.
Term " buffer solution " comprises at least one hydrophilic amino acid or the aminoacid with positively charged side chain, and alkali metal salt, alkali salt or transition metal salt.
Under vantage, buffer solution also comprises at least one hydrophobic amino acid.
Another theme of the present invention comprises the method for the preparation for the treatment of ejection preparation, and described method comprises and is dissolved in water for injection by the solid composite defined herein.
The invention still further relates to the ejection preparation that can sharp obtain in this way.
Detailed Description Of The Invention
The applicant provides at room temperature has chemistry and physical stability, the factor VII composition that the patient being convenient to suffer from particularly hemophilia or congenital factor VII Defect uses.
Specifically, new pharmaceutical compositions of the present invention, under solid form, has the stability more than 24 months at less than or equal to the temperature of 25 DEG C.
Therefore, compositions can the remarkable degraded of not occurrence factor VII in room temperature storage.Term " room temperature " means the temperature in room, generally includes the temperature between 10 DEG C to 30 DEG C, preferably between 15 DEG C to 25 DEG C.
Term " factor Ⅴ II " or " FVII " comprise the polypeptide of the 1-406 sequence of the FVII comprising Wild type human's factor Ⅴ II (as described in patent U.S.4784950) or come from another species (such as cattle, pig, dog, Mus).It also comprises the natural allelic variation of the factor Ⅴ II that may exist, and the glycosylation of any form or degree or other post translational modifications.
Term " factor Ⅴ II " also comprises have FVII variant that is identical or more high bioactivity compared with the activity of wild type FVII, and these variants are particularly including the polypeptide different from wild type FVIIa by one or more amino acid whose insertion, disappearance or replacement.
" factor Ⅴ II " or " FVII " comprise the factor Ⅴ II of FVII (proenzyme) and the activation of not cutting.Factor Ⅴ II preferably uses in the composition with its activated form.
Term " biological activity of factor VIIa " is included in the ability that the platelet surface place such as activated produces thrombin.In compositions, the activity of factor Ⅴ II can be assessed by various mode.Such as, it by the amount of the factor VIIa that uses alcohol coagulation test to measure and can be measured by the ratio between the amount of the factor Ⅴ II of the immunoreaction measurement of anti-FVII antibody.
Term " stable compositions " represents in the production of compositions of the present invention or between the storage life in this article, the formation of aggregation (insoluble or solvable) is minimized, and/or chemical degradation is lowered, pH is maintained and the conformation of albumen does not change substantially, and the biological activity of albumen and stability are kept.When compositions carries out lyophilization, the static stabilization of compositions relates to lyophilizing protection (lyoprotection) and the antifreezing protection of albumen.
" physical stability " of term factor Ⅴ II refers to the minimizing that the insoluble or soluble aggregate of the factor Ⅴ II of dimerization, oligomerization or Multimeric forms is formed or does not exist, and also refers to the minimizing of any structural degeneration of molecule or does not exist.
Term " chemical stability " refers to and is in factor Ⅴ II under solid state or dissolved form between the storage life, under acceleration conditions, and the minimizing of its any chemical modification or do not exist.Such as, hydrolysis, de-amine and/or oxidative phenomena are prevented from or postpone.The oxidation of sulfur-containing amino acid is limited.
Such as, solid composite of the present invention is before preparation method terminates and stores, oxidised form containing low content and aggregation, such as by weight lower than 5%, preferably by weight lower than 4% or lower than 3% or be transformed into oxidised form lower than the FVII of 2%, and by weight lower than 5%, preferably by weight lower than 4% or lower than 3% or be transformed into dimerization or Multimeric forms lower than the FVII of 2%.Between the storage life, in the dark store 24 months at 30 DEG C after, be preferably transformed into oxidised form lower than the FVII of 10% by weight, and be transformed into dimerization or Multimeric forms lower than the FVII of 10% by weight.
Freeze-dried composition of the present invention also shows structural stability, and namely it can be formed unautogenous defeated and dispersed and be easy to the cake (or plug shaped article) that is dissolved in water before use.
Pharmaceutical composition of the present invention is the compositions of the Coverage factor VII taking liquid form or solid form, and described compositions is not containing mannitol and sucrose.
In the present compositions, preferably take the content of the factor Ⅴ II of factor VIIa form can be as follows: between 0.1 to 15mg/ml, preferably between 0.1 to 10mg/ml, more preferably between 0.2 to 5mg/ml, or (preferably measure with the form of injection preparation after reconstitution in liquid form or optionally before it is dried) between 0.2 to 2mg/ml.
Under preferable case, compositions is not containing any sugar, polyhydric alcohol or methionine.
Specifically, the sugar that avoid in addition to sucrose, also comprises disaccharide and trisaccharide and polysaccharide, such as glucose, lactose, maltose, trehalose, cyclodextrin, maltodextrin and glucosan.
Specifically, the polyhydric alcohol that avoid, except mannitol, also comprises Sorbitol and xylitol.
More preferably, in situation, compositions is not containing glycylglycine.
According to a preferred embodiment, compositions of the present invention is not containing any antioxidant.Antioxidant comprises such as one or more following compounds: homocysteine, cysteine, cystathionie, methionine, glutathion.
Compositions of the present invention comprises at least one hydrophilic amino acid or the aminoacid with positively charged side chain, and optionally also comprises at least one hydrophobic amino acid.Hydrophilic (or polarity) aminoacid or comprise lysine, arginine, histidine, glycine, serine, threonine, tyrosine, agedoite and glutamine with the aminoacid of positively charged side chain.
In hydrophilic amino acid or the aminoacid with positively charged side chain, preferably can use the one in arginine or its salt derivative, such as arginine monohydrochloride or argininephosphoric acid salt.
Under vantage, aminoacid such as glycine and/or lysine or its salt derivative such as lysine hydrochloride can be added.
Add hydrophilic amino acid or the aminoacid such as arginine with positively charged side chain, and in applicable situation, add hydrophobic amino acid or even add alkali metal salt, alkali salt or transition metal salt, facilitate the stabilisation of factor Ⅴ II and the dissolving of freeze-dried.
Hydrophobic amino acid (comprising non-polar sidechain) comprises following aminoacid specifically: alanine, valine, leucine, isoleucine, phenylalanine, tryptophan and proline.
Under preferable case, in the background of the invention, hydrophobic amino acid is isoleucine, leucine or both mixture.
Under preferable case, compositions of the present invention comprises alkali metal salt, alkali salt or transition metal salt.Can specifically should be mentioned that trisodium citrate, calcium chloride or zinc chloride.Under preferable case, the salt of use is preferably sodium citrate or calcium chloride.
Finally, compositions of the present invention can comprise one or more non-ionic detergents, such as polysorbate, poloxamer, polyoxyethylene alkyl ether, ethylene/propylene alkene block copolymer and Polyethylene Glycol.Under vantage, preferred detergent is polysorbate 80 and TWEEN-20.
In an embodiment, compositions comprises:
-factor Ⅴ II, it preferably takes the form of factor VIIa;
-arginine, it optionally takes hydrochloride form;
-isoleucine;
-lysine;
-glycine;
-trisodium citrate or calcium chloride;
-and in applicable situation, polysorbate 80 or TWEEN-20.
More particularly, compositions can comprise:
-factor Ⅴ II, it preferably takes the form of factor VIIa;
The arginine of-10 to 40g/l, it optionally takes hydrochloride form;
The isoleucine of-4.2 to 6.6g/l;
The lysine of-0.6 to 1.8g/l;
The glycine of-0.6 to 1.8g/l;
The citrate dihydrate trisodium of-1 to 2g/l or the calcium chloride dihydrate of 0 to 0.2g/L;
-and applicable situation under, the polysorbate 80 of 0 to 0.5g/l.
According to an instantiation, compositions comprises:
The factor Ⅴ II (preferably taking the form of factor VIIa) of-0.2 to 2g/l,
The arginine monohydrochloride of-24g/l,
The isoleucine of-6g/l,
The citrate dihydrate trisodium of-1.5g/l,
The glycine of-1.2g/l,
The lysine hydrochloride of-1.2g/l,
-and/or the polysorbate 80 of 0.07g/l.
According to another specific embodiments, compositions comprises:
The factor Ⅴ II (preferably taking the form of factor VIIa) of-0.2 to 2g/l,
The arginine monohydrochloride of-34g/l,
The calcium chloride dihydrate of-0.15g/l,
The isoleucine of-6g/l.
Concentration be for drying before liquid form or reconstruct after the compositions of injection preparation form measure.
The applicant eliminates sucrose and mannitol from Pharmaceutical composition, and these compositions are often used as diluent or the stabilizing agent of the pharmaceutical preparation of Coverage factor VII.
Sucrose and not existing of mannitol provide several advantage.First, the oxidizing component can introduced by sucrose or endotoxic appearance is avoided.
Show surprisingly, not existing of mannitol allows to prevent from being formed in compositions during lyophilization the polymorph of mannitol crystal, and limits the risk that impurity in compositions, particularly mannose exist.
In addition, unexpectedly, there is not mannitol in the present compositions and the stability of sucrose to compositions does not have adverse effect.On the contrary, observe compositions and obtainable formulation example as
rT compares, the rising of glass transition temperature.
Glass transition is second order trnasition, namely relates to thermal capacity and changes but the heat deflection not relating to latent heat change.
The feature of subcooled liquid is cooled to enough low temperature and non-crystallizable fast enough, and becomes glass and amorphous polymer or enter the pars amorpha of crystalline polymer of visco-elastic state from solid.Temperature when glass transition temperature or Tg are this state change generations.When fluid product is cooled to lower than this temperature, it becomes the glazed solid of class and frangible, is called as and is in glassy state.
Because when product is in glassy state, the mobility of molecule is blocked (only having free radical functional group still to have low relative mobility), be therefore favourable by product stock at lower than the temperature of its glass transition.Therefore, high glass-transition temperature facilitates freeze-dried composition better stability under high temperature (> 25 DEG C), and because this reducing the reactivity [Pikal etc. of active component, formulation parameters is on the impact (The Effectsof Formulation Variables on the Stability of Freeze-Dried Human GrowthHormone) of cryodesiccated human growth hormone's stability, Journal of Pharmaceutical Research, Vol 8, p 427-436,1991].
In addition, by means of its preparation composition, Pharmaceutical composition of the present invention prevents protein aggregation.
In fact, under mannitol and sucrose exist, as
in RT preparation, glass transition temperature is 45 DEG C.Do not contain the glass transition temperature of the compositions of the present invention of sucrose and mannitol higher than 60 DEG C, generally between 74 to 93 DEG C, make it possible to imagination and it is stored (see Fig. 2) outside refrigerator, even at higher than the temperature of 25 DEG C.
Factor Ⅴ II is generally human Factor VII.It can be obtained by various mode, such as, from human plasma can not level part of low-temperature precipitation, or to be obtained from cell or from transgenic animal by genetic engineering.
Under preferable case, the factor Ⅴ II form of factor VIIa (be preferably) produces in the milk of particularly transgenic animal, and preparation of the present invention can make factor Ⅴ II after lyophilization, keep gratifying biological activity.
In a preferred embodiment, human Factor VII genetically modified with the milk of the non-human transgenic animal producing this albumen in produce.Under preferable case, it is the milk of transgenic doe or transgenic goat.
It can be made to secrete in the milk of transgenic animal by mammary gland specific promoter VII, it relates to the expression organizing dependency mode controlling elements VII.Such control method is known concerning the professional of the art.Utilize and allow albumen to control expression towards the sequence that the particular organization of animal expresses.Specifically, they are promoter sequence and signal peptide sequences of WAP, beta-casein and beta lactoglobulin.Method for extracting target protein from the milk of transgenic animal is described in patent EP 0264166.
Compositions of the present invention can use any common technology to obtain.
Specifically, compositions of the present invention can by performing following method to obtain, and described method comprises and mixed with buffer solution by factor Ⅴ II, adjusts pH if necessary, filter to obtain liquid form, then carry out drying if necessary to obtain solid form.
Under preferable case, before dry, the pH of solution is between 4.0 to 9.0, is more in particular in the scope between 4.0 to 8.0,4.0 to 7.5,4.5 to 7.5,5.0 to 7.5,5.5 to 7.0,6.0 to 7.5,6.5 to 7.5.
Drying is the process removing water in a large number.It is intended to the dehydration eliminating water as much as possible.This phenomenon can be natural or enforceable.This drying can utilize lyophilization, spraying dry or low temperature spray drying technology to carry out.Lyophilization for obtaining the method for optimizing of Pharmaceutical composition solid form of the present invention.
Freeze-drying method for the art professional be known, see such as [Wang etc., the exploitation (Lyophilization anddevelopment of solid protein pharmaceuticals) of lyophilization and solid protein pharmaceuticals, International Journal ofPharmaceutics, Vol 203, p 1-60,2000].
It is contemplated that and be suitable for reducing the humidity of compositions or the additive method of moisture.Under preferable case, humidity is less than or equal to by weight 3%, is preferably less than or equal to 2.5%, is preferably less than or equal to 2%, be preferably less than or equal to 1.5%.
Under vantage, can implement for eliminating or the method for inactivation infectious agent, such as, by carrying out dry type heating to lyophilization thing to compositions of the present invention.
Preferably take the solid composite of the present invention of freeze-dried can be dissolved in water for injection (WFI), to obtain therapeutic preparation.
Under preferable case, can be dissolved in pure water by factor Ⅴ II, itself and more complicated reconstruct solvent such as exist
the solvent containing histidine used in RT product is compared advantageously.
Fluid composition of the present invention (before drying) has chemistry or the physical stability of at least 3 days between 2 DEG C to 8 DEG C.
Solid composite of the present invention, under solid form, has at less than or equal to the temperature of 25 DEG C and is greater than 24 months, preferably reaches chemistry or the physical stability of at least 36 months.The ejection preparation of reconstruct is also highly stable, and its chemistry under liquid form and physical stability, be greater than 6 hours, be preferably greater than 12 hours, be preferably greater than 24 hours, more preferably greater than 1 week at 25 DEG C.
The pharmaceutical composition of liquid form or solid form or ejection preparation can be used for treating various pathological condition.
Theme of the present invention is pharmaceutical composition as defined above or ejection preparation, and it is used for the treatment of hemophilia or congenital factor VII Defect.
Also describe the method being used for the treatment of hemophilia or congenital factor VII Defect, wherein to the ejection preparation described by the patient's effective dosage needing to treat.
Hemophilia can be A type or haemophilia B.The feature of haemophilia A is that Factor IX lacks, and haemophilia B part is owing to lacking factors IX.Congenital factor VII Defect by the heredity of autosomal recessive inheritance, AR mode, to be reduced by coagulation factor VII or rare heritability hemorrhagic disease caused by lacking.
Ejection preparation can with amount parenteral (intravenous, subcutaneous, the intramuscular) administration estimated by practitioner.Do not get rid of by any applicable approach and any applicable means administration liquid form (before drying) or solid form.
The following examples and figure describe the present invention, but do not limit its scope.
Marginal data
The figure of Fig. 1 shows preparation F3 and is reconstructing liquid form and after store 6 days at 25 DEG C, the FVIIa activity coming from it is kept.
Preparation F3, F4 and F7 that the figure of Fig. 2 shows solid form between storage life of 1 month, can keep the activity of albumen (FVIIa) (representing with the ratio of FVIIa/FVII: Ag) at 40 DEG C.
Embodiment:
The FVII used in an embodiment obtains from the milk of transgenic doe as described in patent application WO 2008099077.It is by the human Factor VII activated during its purification.
embodiment 1: the preparation of preparation
1.1: the preparation of liquid preparation F1 to F7:
As row corresponding in table 1 define, the factor Ⅴ II (10-20ml) also activated by purification, respectively with the approximate concentration of 0.6mg/ml (preparation F1 to F5) and 0.4mg/ml (preparation F6 and F7), dialyses 12 hours for 2 liters of buffer solution.1M NaOH or 1M HCl is used to adjust pH (6.0 ± 0.2).The FVIIa solution prepared is filtered, and is divided in bottle with the deal of every bottle of 0.5ml.Then bromobutyl plug is used to be clogged in advance by bottle.
1.2: the preparation stemming from the freeze-dried preparation of the liquid preparation F1 to F7 of preparation in 1.1 above:
According to predetermined circulation, lyophilization is carried out to bottle.In order to detect dry end, freezer dryer is equipped with capacitance-type sensor for moisture content.At the end of lyophilization cycle, bottle is clogged under vacuo and uses aluminum envelope encapsulates.
1.3: the preparation of liquid preparation F8:
On Superdex 200 solvent resistant column, prepare purification by buffer-exchanged and the factor Ⅴ II (0.4mg/ml) of activation.First the post buffer solution comprising trisodium citrate (1.0g/l), arginine monohydrochloride (30g/l) and isoleucine (6.0g/l) (is participated in table: F8) balance.Regulate pH (7.0 ± 0.2).The concentration of eluent is about 0.4mg/ml after measured.
The FVIIa solution prepared is filtered, and is divided in bottle with the deal of every bottle of 0.5ml.Then bromobutyl plug is used to be clogged in advance by bottle.
1.4: the preparation stemming from the freeze-dried preparation of the liquid preparation F8 of preparation in 1.3 above:
According to predetermined circulation, lyophilization is carried out to bottle.In order to monitor dry end, freezer dryer is equipped with capacitance-type sensor for moisture content.At the end of lyophilization cycle, bottle is clogged under vacuo and uses aluminum envelope encapsulates.
1.5: the preparation of liquid preparation F9 and lyophilization:
On Superdex 200 solvent resistant column, prepare purification by buffer-exchanged and the factor Ⅴ II (about 0.4mg/ml) of activation.First the post buffer solution comprising trisodium citrate (1.0g/l), arginine monohydrochloride (30g/l) and isoleucine (6.0g/l) (is participated in table: F9) balance.Regulate pH (7.0 ± 0.2).Add glycine (1.2mg/ml) and lysine hydrochloride (1.2mg/ml).
The FVIIa solution prepared is filtered, and is divided in bottle with the deal of every bottle of 1.0ml.Then bromobutyl plug is used to be clogged in advance by bottle.
Then by bottle lyophilization in the same manner as previously described, and 6 months are stored at 40 DEG C.
1.6: the preparation of liquid preparation F10 and F11 and lyophilization:
Dialyse by the pipeline of buffer (see table: F10 and F11) that defines in containing, for example table 3 and 4, prepared concentration respectively and be about the purification of 1.0mg/ml (F10) and 0.8mg/ml (F11) respectively and the factor Ⅴ II of activation.Regulate pH (7.0 ± 0.2).
The FVIIa solution prepared is filtered, and is divided in bottle with the deal of every bottle of 1.0ml.Then bromobutyl plug is used to be clogged in advance by bottle.
Then by bottle lyophilization in the same manner as previously described.
Preparation F10 is stored under the following conditions:
-liquid, stores 144 hours at 5 DEG C, then stores 6 hours at 25 DEG C,
-freezing and thaw cycles (4 continuous circulations),
-lyophilization also stores 6 months at 25 DEG C and 40 DEG C,
-at <-70 DEG C freezing 6 months.
Preparation F11 is stored under the following conditions:
-liquid, stores 72 hours at 5 DEG C, then stores 6 hours further at 25 DEG C,
-lyophilization also stores at 25 DEG C and 40 DEG C,
-be chilled in buffer at <-70 DEG C before dialysis step: trometamol (2.42mg/ml), NaCl (8.77mg/ml) and mannitol (30mg/ml).
embodiment 2: preparation is tested
Materials and methods
2.1. the measurement of the dynamic light scattering of " DLS " is called below
Will from cryodesiccated often kind of sample 500 microlitre be placed in micro cell (
wertheim, Germany), transferred to (Malvern Instruments, Worcestershire, UK) in Zetasizer Nano instrument.This instrument uses the 4mW He-Ne laser instrument of 633nm and Noninvasive backscatter or NIBS technical operation.
Protein monomers colony uses the scattering technology software (Dispersion Technology Software) (4.00 editions) of Malvern to calculate with the distribution of sizes of intensity and stereometer.The refractive index of material and dispersant is decided to be 1.33 and 1.45 respectively.Temperature during measurement is controlled and is fixed on 20 DEG C.The mass parameter of institute's test formulation comprises the diameter of monomeric form protein population and the scattering strength of protein population.
2.2. the visual inspection of reconstituted formula
Test formulation reconstructs from freeze-dried preparation 0.5g water for injection.Syringe is used by stopper, solvent to be injected the bottle of lyophilization thing.
After cake dissolves completely, according to the visual inspection method relevant to European Pharmacopoeia (European Pharmacopoeia), (analytical method---pharmaceutical technology step---particulate pollutant---visible particles---2.9.20 section (Methods of Analysis-Pharmaceutical Technical Procedures-Particulate contamination-visibleparticles-paragraph 2.9.20)) is checked to reconstituted product.
According to the pollution level of visible particles, sxemiquantitative classification is carried out to the preparation of test:
-=without visible particles
ε=very low amount visible particles
+=a small amount of visible particles
++=a large amount of visible particles
The a large amount of visible particles of +++=very
All tests independently and undertaken by three different operating personnel.
2.3. for the filtration test of aggregation detection
The method used obtains [Li etc. from article, for detecting the straightforward procedure (A simple method for the detection of insoluble aggregates inprotein formulations) of insoluble aggregate in protein formulation, Journal of Pharmaceutical Sciences Vol 96 (7), p1840-1843,2007].
Will
the 3ml water cleaning of GV 0.2 μm of non-velum filteration device, then cleans with the buffer solution of same volume.Then albumen (FVIIa) solution to be analyzed for 0.5ml is passed through this metre filter.Then filter used again the water for injection of same volume (3ml), then use buffer solution (3ml) to clean.By adding 2ml staining solution (the reversible protein detection kit (Reversible Protein Detection KIT) from SIGMA), albumen level part that filter is retained is dyeed.Staining solution and filter membrane are kept in touch 5 minutes, then flows.Then again film is cleaned as mentioned above.According to the degree coming from the colouring particles of albumen observed on the filter, sxemiquantitative classification is carried out to test formulation:
-=do not detect comes from the visible particles of albumen
ε=detect that very low amount comes from the visible particles of albumen
+=detect comes from the visible particles of albumen on a small quantity
++=detect comes from the visible particles of albumen in a large number
+++=detect comes from the visible particles of albumen very in a large number
2.4. the mensuration of glass transition temperature (Tg)
The DSC 7 differential scanning calorimeter instrument (Perkin Elmer) using indium (fusing point (Tm) 156.6 DEG C) and n-octadecane (Tm 38.2 DEG C) to calibrate is utilized to measure glass transition temperature.Sample is made to experience the temperature of from-50 to 138 DEG C with the speed of 20 DEG C/min.Helium is used to test at a temperature below the room temperature.Glass transition temperature is taken as the median point place of the change of heat absorption of apparent specific heat.Carry out twice measurement and use meansigma methods as Tg.
2.5.FVIIa/FVII: the mensuration of Ag ratio
Ratio between the amount of the factor VIIa measured by using alcohol coagulation test and the amount of factor Ⅴ II measured by the immunoreactivity of anti-FVII antibody, carrys out the activity of factor Ⅴ II in evaluation group compound.
The mensuration of factor Ⅴ II (being called " factor Ⅴ II antigen " or " FVIIAg " below):
FVII utilizes commercialization reagent (Diagnostica Stago) to use immunoenzymology method (ELISA) to measure.In simple terms, factor Ⅴ II to be determined is immobilized in the anti-human factor Ⅴ II antibody capture in solid phase.Then by factor Ⅴ II that the immune conjugate identification of peroxidase conjugate combines.The activity of substrate o-phenylene diamine is measured to the amount of the peroxidase of combination under aqueous hydrogen peroxide exists by peroxidase.After use strong acid cessation reaction, colored intensity depends on the amount of the initial factor Ⅴ II existed in sample.
The mensuration of the factor FVII of activated form:
The factor FVII (FVIIa) of activation utilizes commercialization reagent (Diagnostica Stago) to use clocking method to measure.Recombinant soluble tissue factor (rsTF) has the cofactor function of factor VIIa, and allows blood plasma condensation under phospholipid and calcium exist.Within the system, the amount of the factor Ⅴ II comprised in test sample will be depended on the setting time of acquisition.Factor Ⅴ II is not activated into factor VIIa by rsTF; Therefore, the factor Ⅴ II not interferometry comprised in blood plasma.
2.6: molecular dimension distribution (MSD):
Molecular dimension distribution utilizes the tomographic system being equipped with pump, constant temperature syringe, UV detector and computer acquisition system, uses Superdex Tricorn 20010/300GL post (GEHealthcare, reference number 17-5175-01) to measure.Mobile phase is made up of the 0.01M phosphate buffer of pH 7.4,0.138M sodium chloride and 0.0027M potassium chloride.Its flow velocity is 04ml/min.For analysis, inject 100 μ l samples.UV detection is carried out at 280nm place.
2.7:SDS-PAGE (reduction/non-reducing):
By under non reducing conditions and reducing condition, in the Novex system (Invitrogen) using the gel in 2-(N-morpholine) ethane sulfonic acid or MES buffer, the difference relative to protein wt is analyzed, to assess the quality of sample in the amount of covalency aggregation and fragment by SDS-PAGE electrophoretic migration.The amount corresponding to 2 μ g albumen is carried out load sample.Albumen is undertaken visual by Coomassie brilliant blue and/or cma staining.
2.8：IEF
Various FVII isoform is undertaken by isoelectrofocusing (IEF) according to the separation of its isoelectric point, IP.Migration, under natural (non-reduced and non denatured) condition, the Focugel 3-10ETC (Gelcompany) in Multiphor system is carried out.Product is carried out desalination on defecator (exclusion size 10kDa).After the OD by 280nm place determines production concentration, by 30 μ g load samples on gel.After with CBB-G250 (Coomassie brilliant blue G250) dyeing to product in the colony's pI standard substance different from two kinds (standard substance from the pI 5.5-10.5 of GE and the pI 5.4-5.9-6.6 standard substance from Sigma that comprise, standard substance are load sample individually) compare, the pI (the Quantity one software of use BioRad is quantitative) of FVII isoform can be identified.
result:
1.
preparation F1 to F8
In table 1 below, provide preparation F1 and F2 for comparing.
In compositions of the present invention (preparation F3 to F8), preparation F3, F4 and F7 are preferred.
According to this table, the percentage intensity (being respectively 58%, 61% and 55%) of the protein monomers colony that preparation F4, F5 and F7 demonstrate higher than
(F1) (9%) and
(F2) the percentage intensity obtained in (27%) preparation.These results reflect the increase of product at solid form stability inferior, and the existence of monomer can reduce immunoreactive risk.
For the ratio of FVIIa/FVII: Ag, preparation F3, F4 and F8 be FVIIa/FVII: the Ag ratio that shows under liquid form before lyophilization and after reconstruct, higher than use formulation example as
and NovoSeven (F1)
(F2) ratio obtained, it reflects the following fact, and albumen (FVIIa) activity namely comprised in compositions of the present invention is higher.Before lyophilization, can observe FVIIa/FVII: Ag ratio for F3 is 17, is 23 for F8, in contrast to this, uses
and NovoSeven (F1)
the ratio that preparation obtains is 14, and after reconstitution under liquid form, can observe FVIIa/FVII: Ag ratio for F3 is 19, is 20 for F8, in contrast to this, uses
and NovoSeven (F1)
the ratio that preparation obtains is 15.
For the experiment carried out glass transition temperature (Tg), preparation F3 to F8 of the present invention demonstrates the increase of glass transition temperature.Specifically, the glass transition temperature of acquisition equals 75 DEG C for preparation F3, for preparation F7, equal 93 DEG C.It is advantageously stable in these formulations that these results demonstrate albumen (FVIIa).This is because high Tg allows the mobility by reducing active component and the reactive stability improving albumen.In addition, these results clearly illustrate, and from NovoNordisk company
product is contrary, and product of the present invention can be stored in outside refrigerator.
For the filtration test detected for aggregation, result shows that preparation F3 to F8 of the present invention demonstrates little aggregation, or for preparation F4, F7 and F8, does not have aggregation even completely.
As shown in fig. 1, the activity coming from the FVII of preparation F3 (after reconstitution under liquid form) is still satisfactory after 6 days, and its activity is at least 80%.
As shown in Figure 2, the activity coming from the FVII of preparation F3 (under solid form) is still satisfactory after one month, and its activity is at least 80% for preparation F3, is at least 90% for preparation F4.
2.
preparation F9 to F11-stability study
The result of the test that these preparations carry out is provided in table 2 below to 4.
2.1 stability studies: preparation F9
Preparation F9, under freeze-dried, also still stablizes after 6 months at 40 DEG C.In addition, result shows, and FVII does not demonstrate the sign of any obvious degradation at 40 DEG C after 6 months.
2.2 stability studies: preparation F10
Can demonstrate the research (table 3) that preparation F10 carries out, FVIIa stablizes 48 hours under liquid form at 5 DEG C.
As what also can see in table 2, preparation F10 keeps stable after four freeze/thaw, and the result obtained proves the degraded that there is not FVII.
Preparation F10, at 25 DEG C or 40 DEG C, also keeps stable after six months.The result display of this research, FVII does not experience any degraded.
Preparation F10 (non-frozen drying) after freezing 6 months, also keeps stable at lower than the temperature of-70 DEG C.The result obtained proves that FVII does not experience any degraded.
2.3 stability studies: preparation F11
Preparation F11 (table 4), under freeze-dried, also keeps stable at 25 DEG C or 40 DEG C after 6 months.The result display of this research, FVII does not experience any degraded.
Preparation F11, under freeze-dried, also keeps at lower than the temperature of-70 DEG C stable after freezing 6 months.The result obtained proves that FVII does not experience any degraded.
The stability study display of preparation F11 under liquid form, FVII adds that 6 hours periods kept stable at 25 DEG C for 72 hours at 5 DEG C.
Claims (13)
1. pharmaceutical composition, described compositions takes liquid or solid form, not containing mannitol, sucrose and glycylglycine, comprises:
-factor Ⅴ II, described factor Ⅴ II is in activated form (FVIIa), and is obtained from cell or from transgenic animal by genetic engineering;
The arginine of-10 to 40g/l;
The isoleucine of-4.2 to 6.6g/l;
The lysine of-0.6 to 1.8g/l;
The glycine of-0.6 to 1.8g/l;
The citrate dihydrate trisodium of-1 to 2g/l or the calcium chloride dihydrate of 0 to 0.2g/L;
Wherein said pharmaceutical composition, under solid form, has the stability more than 24 months at less than or equal to the temperature of 25 DEG C.
2. the compositions of claim 1, wherein arginine is hydrochloride form.
3. the compositions of claim 1, wherein lysine is hydrochloride form.
4. the compositions of any one of claims 1 to 3, described compositions is not containing any sugar, polyhydric alcohol or methionine.
5. the compositions of any one of claims 1 to 3, it also comprises polysorbate 80 or TWEEN-20.
6. the compositions of claim 5, it also comprises the polysorbate 80 of the highest 0.5g/l.
7. the compositions of claim 6, it comprises:
The factor Ⅴ II of-0.2 to 2g/l, described factor Ⅴ II is in activated form (FVIIa),
The arginine monohydrochloride of-24g/l,
The isoleucine of-6g/l,
The citrate dihydrate trisodium of-1.5g/l,
The glycine of-1.2g/l,
The lysine hydrochloride of-1.2g/l, and
The polysorbate 80 of-0.07g/l.
8. the compositions of any one of claims 1 to 3, it comprises:
The factor Ⅴ II of-0.2 to 2g/l, described factor Ⅴ II is in activated form (FVIIa),
The arginine monohydrochloride of-34g/l,
The calcium chloride dihydrate of-0.15g/l,
The isoleucine of-6g/l.
9. cryodesiccated solid composite, it can obtain from the compositions of any one of claim 1 to 8.
10. for the preparation of the method for the pharmaceutical composition of any one of claim 1 to 9, described method comprises and is mixed with buffer solution by the factor Ⅴ II be under activated form (FVIIa), regulate pH if necessary, filter, then carry out drying to obtain solid form if necessary.
11. for the preparation of the method for the treatment of ejection preparation, and described method comprises and is dissolved in water for injection by the solid composite defined in any one of claim 1 to 8.
12. ejection preparations, it can be obtained by the method for claim 11.
The pharmaceutical composition of 13. any one of claim 1 to 8 or the application of the ejection preparation of claim 12 in the medicine for the preparation for the treatment of hemophilia or congenital factor VII Defect.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510137928.9A CN105106943A (en) | 2009-06-26 | 2010-06-18 | Factor vii composition |
Applications Claiming Priority (3)
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|---|---|---|---|
| FR0954390A FR2947181B1 (en) | 2009-06-26 | 2009-06-26 | FACTOR VII COMPOSITION |
| FR0954390 | 2009-06-26 | ||
| PCT/FR2010/051229 WO2010149907A1 (en) | 2009-06-26 | 2010-06-18 | Factor vii composition |
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| CN201080028582.4A Active CN102458455B (en) | 2009-06-26 | 2010-06-18 | Factor vii composition |
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| EP (2) | EP2445516B1 (en) |
| JP (3) | JP5706888B2 (en) |
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| EP2275432A1 (en) | 2003-12-01 | 2011-01-19 | Novo Nordisk Health Care AG | Nanofiltration of factor VII solutions to remove virus |
| FR2947181B1 (en) * | 2009-06-26 | 2012-05-04 | Lfb Biotechnologies | FACTOR VII COMPOSITION |
| EP3834851A1 (en) | 2010-12-30 | 2021-06-16 | Laboratoire Français du Fractionnement et des Biotechnologies | Glycols as pathogen inactive agents |
| EP2687595B1 (en) | 2012-07-19 | 2018-05-30 | Laboratoire Français du Fractionnement et des Biotechnologies | Method for purifying transgenic factor VII |
| FR3006591B1 (en) | 2013-06-11 | 2016-05-06 | Lab Francais Du Fractionnement | FACTOR VII COMPOSITION HAVING A SUBSTANTIALLY HOMOGENEOUS ISOELECTRIC POINT |
| EP3307237A1 (en) | 2015-06-12 | 2018-04-18 | Laboratoire Français du Fractionnement et des Biotechnologies | Injectable composition of factor vii and fillers |
| ES2963725T3 (en) * | 2016-07-11 | 2024-04-01 | Opko Biologics Ltd | Long-acting coagulation factor VII and methods of producing the same |
| FR3082427B1 (en) | 2018-06-14 | 2020-09-25 | Lab Francais Du Fractionnement | COMBINATION OF FACTOR VII AND A BISPECIFIC ANTIBODY ANTI-FACTORS IX AND X |
| US20210069306A1 (en) | 2019-08-15 | 2021-03-11 | Catalyst Biosciences, Inc. | Modified factor vii polypeptides for subcutaneous administration and on-demand treatment |
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| WO2001012653A1 (en) * | 1999-08-17 | 2001-02-22 | Novo Nordisk A/S | Stabilisation of freeze-dried cake |
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| WO2008113589A1 (en) * | 2007-03-20 | 2008-09-25 | Csl Behring Gmbh | Methods for industrial scale production of therapeutic complement factor h preparations from human plasma |
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| GR860984B (en) | 1985-04-17 | 1986-08-18 | Zymogenetics Inc | Expression of factor vii and ix activities in mammalian cells |
| DE122007000007I1 (en) | 1986-04-09 | 2007-05-16 | Genzyme Corp | Genetically transformed animals secreting a desired protein in milk |
| JP3543144B2 (en) * | 1995-03-11 | 2004-07-14 | 国際試薬株式会社 | Formulation for clinical test |
| DE19538687A1 (en) * | 1995-10-17 | 1997-04-24 | Boehringer Mannheim Gmbh | Stable pharmaceutical dosage forms containing parathyroid hormone |
| JP4455802B2 (en) * | 2000-05-03 | 2010-04-21 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | Human VII coagulation factor variant |
| JP2005526004A (en) * | 2001-11-09 | 2005-09-02 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | A pharmaceutical composition comprising a Factor VII polypeptide and tranexamic acid |
| AU2003240438A1 (en) | 2002-06-21 | 2004-01-06 | Novo Nordisk A/S | Stabilised solid compositions of factor vii polypeptides |
| CN1839203B (en) * | 2003-06-19 | 2011-11-16 | 拜耳医药保健有限公司 | FVII or FVIIa GLA domain variants |
| FR2857267B1 (en) * | 2003-07-09 | 2006-03-10 | Lab Francais Du Fractionnement | STABILIZING AND SOLUBILIZING FORMULATION FOR CRYOPRECIPITABLE PROTEINS. |
| EP1855722A2 (en) * | 2005-02-24 | 2007-11-21 | Novo Nordisk Health Care AG | Compounds for stabilizing factor vii polypeptide formulations |
| KR101364003B1 (en) * | 2005-04-28 | 2014-02-21 | 노보 노르디스크 헬스 케어 악티엔게젤샤프트 | A closed container comprising an activated factor vii polypeptide, processes for the preparation of the same, and a kit and a method for use of the kit |
| US20090017007A1 (en) * | 2005-08-26 | 2009-01-15 | Maxygen Holdings Ltd. | Liquid factor vii composition |
| FR2894831B1 (en) * | 2005-12-16 | 2008-02-15 | Lab Francais Du Fractionnement | THROMBIN FREE BIOLOGICAL GLUE AND USE THEREOF AS MEDICAMENT. |
| CA2673260A1 (en) * | 2006-12-20 | 2008-07-03 | Bayer Healthcare Llc | Factor vii and viia compositions |
| FR2910786B1 (en) | 2006-12-29 | 2017-08-11 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies (Lfb) | "PROCESS FOR EXTRACTING A PROTEIN PRESENT IN MILK" |
| JP2010525034A (en) * | 2007-05-02 | 2010-07-22 | ノボ ノルディスク ヘルス ケア アーゲー | Highly concentrated factor VII polypeptide formulation comprising an aromatic preservative and an antioxidant |
| FR2947181B1 (en) * | 2009-06-26 | 2012-05-04 | Lfb Biotechnologies | FACTOR VII COMPOSITION |
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| WO2001012653A1 (en) * | 1999-08-17 | 2001-02-22 | Novo Nordisk A/S | Stabilisation of freeze-dried cake |
| CN1845753A (en) * | 2003-08-14 | 2006-10-11 | 诺和诺德医疗保健公司 | Liquid, aqueous, pharmaceutical compositions of factor vii polypeptides |
| WO2008113589A1 (en) * | 2007-03-20 | 2008-09-25 | Csl Behring Gmbh | Methods for industrial scale production of therapeutic complement factor h preparations from human plasma |
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